2-(2-aminophenyl)isoindolines



United States Pat ent 3,466,297 2-(2-AMINOPHENYL)ISOINDOLINES TheodoreS. Sulkowski, Narberth, and Albert A. Mascitti,

Norristown, Pa., assignors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Filed Mar. 14, 1967,Ser. No. 622,920 Int. Cl. C07d 27/56; A61k 27/00 US. Cl. 260-326.1 8Claims ABSTRACT OF THE DISCLOSURE The present invention is concernedwith 2-(2-arninophenyl)phthalimidines and 2-(2-aminophenyl)isoindolines.These 2-(Z-aminophenyl)phthalimidines are useful intermediates in thepreparation of their corresponding 2-(2-aminophenyl)isoindolines whichare pharmacologically eflicacious as anti-convulsants.

This invention relates to new and novel phthalimidines and isoindolines.In particular, the present invention is concerned with2-(Z-aminophenyl)phthalimidines which are useful intermediates in theproduction of 2-(2-aminophenyl)isoindolines which have demonstratedpharmacological activity and are useful as anti-convulsants.

The novel compounds which are included within the scope of thisinvention are represented by the following formula:

wherein R is selected from the group consisting of amino, halogen, halo(1ower)alkyl, lower alkoxy and lower alkyl; R is selected from the groupconsisting of lower alkyl, phen(lower)alkyl, phenyl, aminophenyl,halophenyl, halo (lower)alkylphenyl, lower alkoxyphenyl, loweralkylphenyl, thienyl, pyridyl, and furyl; R and R are selected from thegroup consisting of hydrogen and halogen; X is selected from the groupconsisting of methylene and carbonyl; and the acid addition saltsthereof.

The new compounds of the aforesaid formula where X is carbonyl arecalled Z-(Z-aminophenyl)phthalimdines. Typical examples thereof are:2-(2-aminophenyl)-3- phenylphthalimidine;2-(2-amino-4,S-dichlorophenyl)-3- phenylphthalimidines; and 2 (2 amino4,5 dibromophenyl)-3-phenylphthalimidine. Alternatively when X ismethylene, the compounds are called Z-(Z-aminophenyl) isoindolines, suchas, 2-(2-aminophenyl)-1-phenylisoinline;2-(2-amino-4,S-dichlorophenyl)-1-phenylisoindoline and2-(2-amino-4,S-dibromophenyl) -1-phenylisoindoline.

The new and novel 2-(Z-aminophenyl)phthalimidines andZ-(Z-aminophenyl)isoindolines of the present inven- 3,466,297 PatentedSept. 9, 1969 tion are prepared by the process which is illustrated bythe following reaction scheme:

(III) wherein R R R and R are defined as above.

The hydrogenolysis reaction is efli'ected by contacting anisoindolobenzimidazolone (I) with a palladium charcoal catalyst, in anappropriate solvent, e.g., an alkanol or acetic acid, under a positivehydrogen atmosphere with stirring until the hydrogen uptake ceases.Preferably this reaction is conducted with a 10% palladium on charcoalcatalyst in acetic acid under about 45 p.s.i. of hydrogen pressure.

When the hydrogenolysis reaction is complete, the intermediate (II) isseparated by procedures well known in the art, for xample, the catalystis removed by filtration or decantation; the filtrate evaporated todryness; the residue dissolved in water, basified with a base, e.g.sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassiumbicarbonate; extracted with a Waterimmiscible solvent, for example,ethyl acetate, ether, chloroform, carbon tetrachloride and benzene; andthe extract evaporated to dryness to atford a2-(2-aminophenyl)phtha1imidine (II). It should be noted that thishydrogenolysis reaction will also convert any nitro substituent presenton the isoindolobenzimidazolone (II) to the corresponding aminosubstituent on the resulting 2-(2- aminophenyl)isoindoline (III).

Hydride reduction of the above prepared 2-(2-aminophenyl)phthalirnidine(II) is accomplished by contact with lithium aluminum hydride, in ananhydrous, reaction-inert organic solvent, at a temperature range ofabout 35 C. to about C. for a period of about three to about fifteenhours. Preferably this reaction is conducted in ether at about thereflux temperature of the reaction mixture for a period of about fivehours.

When the hydride reduction is completed, the resulting2-(2-aminophenyl)isoindoline (III) is recovered by conventional means,such as, concentration and recrystallization from a suitable solvent,such as an aqueous alkanol, chloroform-hexane, benzene-hexane andtoluenehexane.

Since many of the compounds prepared by the present invention are basic,advatnage may be taken of the water solubility of salts of thesecompounds formed with acids in the isolation and/or purification of theabove compounds and in the preparation of aqueous solutions of these newcompounds for oral or parenteral administration. Of course, only saltsformed with pharmaceutically acceptable acids should be employed intherapeutic applications. Particularly effetcive salts are those formedwith pharmaceutically acceptable acids having a pK value of 3 or lower.Such acids are well known in the art, for example, hydrochloric,hydrobromic, sulfuric, nitric, phosphoric, benzenesulfonic,toluenesulfonic, methanesulfonic, ethanesulfonic acids and the like.These salts may be prepared by procedures commonly employed in the art,for example, reacting the compounds with an equivalent of the selectedacid in aqeuous solution and concentration of the solution. Other knownprocedures may also be employed.

The time and temperature ranges employed in the aforesaid hydridereduction reaction is not critical but simply represents the mostconvenient range consistent with carrying out the reaction in a minimumof time without undue difficulty. Thus, reaction temperaturesappreciably below these can be used, but their use considerably extendsthe reaction time. Similarly, reaction temperatures higher than thosementioned can be employed with a concomitant decrease in reaction time.By palladium charcoal catalyst as employed herein is meant a catalystconsisting of about two percent to about ten percent palladium oncharcoal. The term positive hydrogen atmosphere is defined to mean ahydrogen atmosphere under a positive pressure of about 15 p.s.i. toabout 75 p.s.i. and the term anhydrous, reaction-inert organic solventincludes any water-free organic which will dissolve the2-(Z-aminophenyl)phthalimidine (II) but will not interfere with thehydride reduction thereof. Many such solvents are well known to thoseskilled in the art of organic chemistry, examples are: ether,tetrahydrofuran, dioxan and diethylene glycol dimethyl ether.

The isoindolobenzimidazolone reactants (I) employed in the preparationof the compounds of the present invention are known compounds which aredescribed and claimed in copending US. Patent Application, Ser. No.523,930, filed on Feb. 1, 1966, entitled Substituted Dihydro1lH-Isoindolo[2,1-a]Benzimidazol-1l-Ones and Related Compounds and nowUS. Patent No. 3,423,421.

In accord with the present invention the novel 2-(2-.aminophenyl)phthalimidines (II) herein described are utilized asintermediates in the preparation of the 2-(2- aminophenyl)isoindolinesof the present invention.

In further accord with the present invention, the novel2-(2-aminophenyl)isoindolines (II) herein described have been found topossess interesting pharmacological properties in mice. In standardpharmacological tests, e.g., electrical shock, using mice as theexperimental animal, these compounds have exhibited anti-convulsantactivity at .a dosage level of 125 mg./kg.

When the compounds of this invention are employed for the aforesaidpurposes, they may be administered alone or in combination withacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard testing practice. They may be administeredorally or injected parenterally, that is intramuscularly, intravenouslyor subcutaneously. For parenteral administration they may be used in theform of a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The following examples are given by way of illustration.

Example I A mixture of 25 g. of 4b-phenyl-4b,5-dihydro-11H-isoindolo[2,1-a1benzimidazol-1l-one, 5 g. of pallasolvent dium oncharcoal and 200 ml. of acetic acid is shaken with hydrogen at aninitial pressure of 43 p.s.i. After the hydrogen uptake ceases (withinone hour), the catalyst is separated by filtration and the filtrateevaporated to dryness. The solid residue is dissolved in water and madebasic with sodium hydroxide solution. The mixture is extracted withethyl acetate. After drying over magnesium sulfate, the extract isevaporated in vacuo to afford 2-(2- aminophenyl)-3-phenylphthalimidine,M.P. 190l92 C.

Twelve grams of 2(2-aminophenyl)-3-phthalimidine are added to a stirredsuspension of 6 g. of lithium aluminum hydride in 400 ml. of anhydrousether and heated to reflux for five hours. After the mixture isdecomposed by careful addition of water, the ether layer is separated,dried over magnesium sulfate, and evaporated to dryness. Onrecrystallization of the residue from ethyl acetatehexane, there isobtained Z-(laminophenyl)-1-phenylisoindoline, M.P. 128130 C.

Analysis.-C.alcd for C H N C, 83.88; H, 6.33; N, 9.79. Found: C, 83.80;H, 6.61; N, 10.07.

In the same manner,S-iodo-4b-(4-trifluoromethylphenyl)-4b,5-dihydro-1lH-isoindolo[2,1-a]benzimidazolll-one is converted to2-(2-amino-5-iodophenyl)-3-(4-trifiuoromethylphenyl)phthalimidine whichis then subjected to hydride reduction to yield2-(2-amino-5-iodophenyl)-1- (4-trifluoromethylphenyl)isoindoline.

Example II A mixture of 12.5 g. of 7,8-dichloro-4b-phenyl-4b,5-dihydro-llH-isoindolo[2,l-a] benzimidaZol-ll-one, 5 g. of 5% palladiumon charcoal and 100 ml. of acetic acid is shaken with hydrogen at aninitial pressure of p.s.i. After the hydrogen uptake ceases, thecatalyst is separated byfiltration and the filtrate evaporated todryness. The solid residue is dissolved in water, made basic withpotassium hydroxide solution and extracted with chloroform. After dryingover magnesium sulfate, the extract is evaporated to afford2-(2-aminc-4,5-dichlorophenyl)phenylphfhalimidine.

Six grams of the above prepared2-(2-amino-4,5-dichlorophenyl)-3-phenylphthalimidine are added to astirred suspension of 3 g. of lithium aluminum hydride in 200 ml. ofanhydrous dioxan and heated to C. for three hours. After the mixture isdecomposed by careful addition of water, the dioxan layer is separated,dried over magnesium sulfate, and evaporated to dryness. Onrecrystallization of the residue from aqueous ethanol, there is obtained2 (2 amino 4,5 dichlorophenyl)-lphenylisoindoline.

Similarly, 7,8-dibr0mo-4b-phenethyl-4b,S-dihydro-11H-isoindolo[2,1-a]benzimidazol-ll-one is converted to 2-(2- amino-4,5dibromophenyl) 3 phenethylphthalimidine which is then subjected tohydride reduction to afford 2-(Z-amino-4,5-dibromophenyl)-1-phenylisoindoline.

Example III Starting material Intermediate Product benzimidazol-l l-one.

benzirnidazol-ll-one.

bonzimidazol-ll-oue.

benzimidazol-ll-one.

2-(2-aminopl1enyl)3- (4-chlorophenyl) phthalimidine.

2-(2-amino-4- bromophenyl)3- (4-bromophenyl)- phthalimidiuc.

2-(2-aminophenyD-3- (a-thienyD- phthalimidine.

2-(2-aminoplrenyl)-6- nmino-3-furylphthalimidine.

2-(2-aminophonyD-1- (4-chlorophenyl) isoindoline.

2-(2-amin0-4- bromophouyD-l- (4hromophonyl)- isoindoline.

2-(2-aminophonyl)-1- (a-thienyD- isoindoline.

2-(2-amin0phenyD-5- amino-l-furylisoiudoline.

Starting material Intermediate Product 2-(2-arninophenyD-5-chloro-3-pyridylphthalimidine.

2-(2-aminophenyD-6- dichlormethy13- phenylphthalimidine.

2-(2-aminophenyD-3- methylphthalimidine.

2-(2-aminophenyD-6 eh10ro-1-pyridylisoindoline.

2-(2-aminophenyl)-5- dichloromethyl-lphenylisoindoline.

Z-(Z-aminophenyD-lmethylisoindoline.

A mixture of 25 g. of4b-benzyl-4b,5-dihydro-l1H-isoindolo[2,1-a]benzimidazol-ll-one, 25 g. of2% palladium on charcoal and 200 ml. of acetic acid is shaken withhydrogen at an initial pressure of 15 p.s.i. After the hydrogen uptakeis complete, the catalyst is separated by filtration and the filtrateevaporated to dryness. The solid residue is dissolved in Water, madebasic With sodium bicarbonate solution and the mixture is extracted withbenzene. After drying over magnesium sulfate, the extract is evaporatedin vacuo to afford 2-(2aminophenyl)-3-benzylphthalimidine.

Three grams of Z-(Z-aminophenyl) 3 -benzylphthalimidine are added to astirred suspension of 1.5 g. of lithium aluminum hydride in 100 ml. ofanhydrous tetralrydrofuran and heated to reflux for seven hours. Afterthe mixture is decomposed by careful addition of water, thetetrahydrofuran layer is separated, dried over magnesium sulfate, andevaporated to dryness. On recrystallization of the residue fromchloroform-hexane, there is obtainedZ-(Z-aminophenyl)-l-benzylisoindoline.

Similarly, Z-(Z-aminophenyl) 6-methoxy-3-(4-aminophenyl)phthalimidineand 2-(2-amino -iodophenyl)-3- phenylphthalimidine are produced and thenrespectively converted to Z-(Z-aminophenyl)5-methoxy-l-(4-aminophenyl)isoindoline and 2-(2-amino 5 iodophenyl)-1-phenylisoindoline.

Example V A mixture of 50 g. of 4b-(4-chlorophenyl)-3-pr0poxy-4b,5-dihydro 11I-I-isoindolo[2,l-a]benzimidazol-1l-one, 10 g. of 10%palladium on charcoal and 400 ml. of acetic acid is shaken with hydrogenat an initial pressure of 50 p.s.i. After the hydrogen uptake ceases,the catalyst is separated by filtration and the filtrate evaporated todryness. The solid residue is dissolved in water and made basic withpotassium bicarbonate solution. The mixture is extracted with ethylacetate. After drying over magnesium sulfate, the extract is evaporatedin vacuo to afford Z-(Z-aminophenyl) 3 (4-chlorophenyl)-5-pr0-poxyphthalimidine.

Twelve grams of the above preparedZ-(Z-aminophenyl)-3-(4-chlorophenyl)phthalimidine are added to a stirredsuspension of 6 g. of lithium aluminum hydride in 400 ml. of anhydrousdiethylene glycol dimethyl ether and heated to reflux for five hours.After the mixture is decomposed by careful addition of Water, thediethylene glycol dimethyl ether layer is separated, dried overmagnesium sulfate, and evaporated to dryness. On recrystalilzation ofthe residue from benzene-hexane, there is obtained2-(2-aminophenyl)-1-'(4-chlorophenyl)isoindoline.

In the same manner, 4b-(4-dichloromethylphenyl)-4b, S-dihydro 11Hisoindolo[2,l-a]benzimidazol-ll-one is converted to 2-(2-aminophenyl) 3(4-dichloromethylphenyl)phthalimidine which is then contacted withlithium aluminum hydride to afford 2-(2-aminophenyl)-1-(4-dichloromethylpheny] isoindoline.

Example VI A mixture of 25 g. of3-methyl-4b-(4-tolyl)-4b,5-dihydro-l1H-isoindolo[2,1-a]benzimidazol-ll-one,5 g. of 10% palladium on charcoal and 200 ml. of acetic acid is shakenwith hydrogen at an initial pressure of 50 p.s.i. After the hydrogenuptake ceases (Within one hour), the catalyst is separated by filtrationand the filtrate evaporated to dryness. The solid residue is dissolvedin water and made basic with sodium hydroxide solution. The mixture isextracted with chloroform. After drying over magnesium sulfate, theextract is evaporated in vacuo to afford 2-(2-aminophenyl) 5methyl-3-(4-tolyl)phthalimidine.

Six grams of Z-(Z-aminophenyl)-5-methyl-3-(4-tolyl) phthalimidine areadded to a stirred suspension of 3 g. of lithium aluminum hydride in 200ml. of anhydrous ether and heated to 35 C. for fifteen hours. After themixture is decomposed by careful addition of water, the ether layer isseparated, dried over magnesium sulfate, and evaporated to dryness. Onrecrystallization of the residue from toluene-hexane, there is obtained2-(2-aminophenyl)6-methyl'l-(4-tolyl)isoindoline.

Similarly, 2-ethyl-4b-phenyl 4b,5'dihydro-llH-isoindolo[2,l-a]benzimidazole-ll-one is converted to 2-(2-aminophenyl)-6-ethyl 3 phenylphthalimidine which is then contacted withlithium aluminum hydride to produce2-(2-aminophenyl)-5-ethyl-l-phenylisoindoline.

Example VII A mixture of 75 g. of 4b-benZyl-3-propyl-4b,5-dihydro-11H-isoindolo[2,l-a]benzimidazol-ll-one, 15 g. of 10% palladium oncharcoal and 600 ml. of acetic acid is shaken with hydrogen at aninitial pressure of 45 p.s.i. After the hydrogen uptakeceases, thecatalyst is separated by filtration and the filtrate evaporated todryness. The solid residue is dissolved in water and made basic withsodium hydroxide solution. The mixture is extracted with ethyl acetate.After drying over magnesium sulfate, the extract 1s evaporated in vacuoto afford 2-(2-aminophenyl)-3- benzyl-S-propylphthalimidine.

Twenty-four grams of the above prepared 2-(2-amin0-phenyl)-3-benzyl-5-propylphthalimidine are added to a stirred suspensionof 12 g. of lithium aluminum hydride in 800 ml. of anhydrous ether andheated to reflux for five hours. After the mixture is decomposed bycareful addition of water, the ether layer is separated, dried overmagnesium sulfate, and evaporated to dryness. On recrystallization ofthe residue from ethyl acetate-hexane, there is obtained2-(2-aminophenyl)-1-benzyl-6-propylisoindoline. Similarly,4b-(4-ethoxyphenyl)-4 b,5-dihydro-1lH-isomdolo[2,1-a]benzimidazol ll-oneis converted to 2-(2 aminophenyl)-3-(4-ethoxyphenyl)phthalimidine whichis then subjected to hydride reduction to afford 2-(2-aminophenyl) -1-(4-ethoxyphenyl) isoindoline.

What is claimed is:

1. A compound selected from the group consisting of those having theformula:

wherein R is selected from the group consisting of amino, halogen,halo(lower)alkyl, lower alkoxy and lower alkyl; R is selected from thegroup consisting of lower alkyl, phen(lower)alkyl, phenyl, aminophenyl,halophenyl, halo(lower)alkylphenyl, lower alkoxyphenyl, loweralkylphenyl, thienyl, pyridyl, and furyl; R and R are selected from thegroup consisting of hydrogen and halogen and the acid addition saltsthereof. References Clted 2. 2-(2-aminopheny1)-1-pheny1isoindoline.UNITED STTATES PATENTS 3.2-(2-amino-4,S-dichlorophenyD-l-phenylisodinoline. 3379'733 4/1968Houhhan 260326'1 gi-(a n il gi i sp iyn j ie 5 ALEX MAZEL, PrimaryExaminer -ammop eny enzy lSOll'l oine. 6.2(Z-aminophenyl)-1-(4-chioropheny1)isoindoline. NARCAVAGE AssistantExammer 7. Z-(Z-aminophenyl)-6-methy1-1-(4-toly1)isoindoiine. US. Cl.X.R. 8. 2-(2-aminopheny1)-1 benzy1-6-propylis0indo1ine. 10 26() 296,309.2, 325; 424-263, 274

